ABSTRACT There is a critical need to accelerate and sustain the adoption of evidence-based strategies (EBS) for Human Papillomavirus (HPV) vaccination into safety-net healthcare settings given the suboptimal vaccination rates in recommended age groups (11-12 years) and persistent disparities in cervical and other HPV-associated cancers among low-income, racial/ethnic minority populations. Although recommended EBS to improve HPV vaccination are available, few studies have fully examined the interrelationships among provider, clinic, and health system levels that enable or inhibit successful integration of EBS for HPV vaccination into routine clinical care. The proposed four-year sequential mixed-methods study seeks to (1) identify factors at multiple levels that are associated with implementation of EBS and (2) improve suboptimal HPV vaccination uptake for underserved adolescents within safety-net settings. Guided by the Practice Change Model, we will engage stakeholders to systematically and comprehensively examine implementation of actionable EBS for HPV vaccination and apply findings in a demonstration study of three purposively selected clinic sites within an urban, multi-site federally qualified health center (FQHC). We then use the Reach, Effectiveness, Adoption, Implementation and Maintenance (RE-AIM) framework to characterize and understand the implementation of EBS for HPV vaccination in demonstration clinic sites. The study will: identify how diverse stakeholders view, prioritize, and adapt actionable provider, clinic and system-level EBS for increasing HPV vaccination through depth interviews and concept mapping (Aim 1); conduct a demonstration project to implement actionable EBS, identified from Aim 1, through practice-facilitated approaches in a purposive sample of three clinic sites within a multi-site FQHC system (Aim 2); and examine practice-based factors associated with implementation of EBS for HPV vaccination using practice observation, depth interviews, and surveys with physicians, clinic staff, and FQHC leaders (Aim 3). Successful implementation of healthcare setting-based EBS to increase HPV vaccination will require a systematic understanding of dynamic relationships within and between healthcare settings that influence practice change. Study findings will identify critical motivators and barriers to translating EBSs for HPV vaccination in safety-net settings and inform the processes needed to prioritize, adapt, and implement EBS for practice change within the safety-net context. The study also establishes an opportunity for subsequent examination of maintenance and scale-up of EBS across practice sites, to be assessed in a longer follow-up period, as well as a foundation for a larger trial to be conducted with more clinics across varying healthcare settings.